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Principal Investigator: Aravind Iyer
Organization: NATIONAL LIBRARY OF MEDICINE
Fiscal Year: 2020
Award: $1,458,093
Funding agency: National Library of Medicine
The origin of eukaryotes was marked by the emergence of several novel subcellular systems. One such is the calcium (Ca2+)-stores system of the endoplasmic reticulum, which profoundly influences diverse aspects of cellular function including signal transduction, motility, division, and biomineralization. We used comparative genomics and sensitive sequence and structure analyses to investigate the evolution of this system. Our findings reconstruct the core form of the Ca2+-stores system in the last eukaryotic common ancestor as having at least 15 proteins that constituted a basic system for facilitating both Ca2+ flux across endomembranes and Ca2+-dependent signaling. We showed that the key EF-hand Ca2+-binding components had their origins in a likely bacterial symbiont other than the mitochondrial progenitor, whereas the protein phosphatase subunit of the ancestral calcineurin complex was likely inherited from the asgardarchaeal progenitor of the stem eukaryote. This further points to the potential origin of the eukaryotes in a Ca2+-rich biomineralized environment such as stromatolites. We further show that throughout eukaryotic evolution there were several acquisitions from bacteria of key components of the Ca2+-stores system, even though no prokaryotic lineage possesses a comparable system. Further, using quantitative measures derived from comparative genomics we show that there were several rounds of lineage-specific gene expansions, innovations of novel gene families, and gene losses correlated with biological innovation such as the biomineralized molluscan shells, coccolithophores, and animal motility. The burst of innovation of new genes in animals included the wolframin protein associated with Wolfram syndrome in humans. We showed for the first time that it contains previously unidentified Sel1, EF-hand, and OB-fold domains, which might have key roles in its biochemistry.
HMCES (5hmC binding, embryonic stem cell-specific-protein) was originally identified as a protein capable of binding 5-hydroxymethylcytosine (5hmC), an epigenetic modification generated by TET proteins. Our work showed that it contains a catalytic triad that is likely to possess autopeptidase activity. This active site was also reported to covalently crosslink to DNA at abasic sites via its conserved cysteine. In a collaboration with Dr. Anjana Rao's lab we showed that Hmces-deficient mice display normal hematopoiesis without global alterations in 5hmC. HMCES specifically enables DNA double-strand break repair through the microhomology-mediated alternative-end-joining (Alt-EJ) pathway during class switch recombination (CSR) in B cells, and HMCES deficiency leads to a significant defect in CSR. HMCES mediates Alt-EJ through its SOS-response-associated-peptidase domain (SRAPd), a function that requires DNA binding but is independent of its autopeptidase and DNA-crosslinking activities. We showed that HMCES is recruited to switch regions of the immunoglobulin locus and provide a potential structural basis for the interaction of HMCES with long DNA overhangs generated by Alt-EJ during CSR. Our studies provided strong evidence for for HMCES as a novel player in eukaryotic DNA repair with an origin in bacteria.
The novel coronavirus (SARS-CoV-2) is the causative agent of an emergent severe respiratory disease (COVID-19) in humans that has resulted in a global health crisis. By using genomic, sequence, structural and evolutionary analysis, we identified several rapidly evolving proteins in SARS-CoV-2 with potential roles in pathogenesis. In addition to the well-known spike protein, these include the triad of Macro domains predicted to process NAD+ an showed that Alpha- and Beta-CoVs possess several novel families of immunoglobulin (Ig) domain proteins, including ORF8 and ORF7a from SARS-related coronaviruses and two protein groups from certain Alpha-CoVs. Among them, ORF8 is distinguished in being rapidly evolving, possessing a unique insert and a hypervariable position among SARS-CoV-2 genomes in its predicted ligand-binding groove. We also uncovered many Ig proteins from several metazoan viruses, which are distinct in sequence and structure but share an architecture comparable to that of CoV Ig domain proteins. Hence, we propose that deployment of Ig domain proteins is a widely-used strategy by viruses, and SARS-CoV-2 ORF8 is a potential pathogenicity factor which evolves rapidly to counter the immune response and facilitate the transmission between hosts.
Social cellular aggregation or multicellular organization pose increased risk of transmission of infections through the system upon infection of a single cell. The generality of the evolutionary responses to this outside of Metazoa remains unclear. We discovered several thematically unified, remarkable biological conflict systems preponderantly present in multicellular prokaryotes. These combine thresholding mechanisms utilizing NTPase chaperones (the MoxR-vWA couple), GTPases and proteolytic cascades with hypervariable effectors, which vary either by using a reverse transcriptase-dependent diversity-generating system or through a system of acquisition of diverse protein modules, typically in inactive form, from various cellular subsystems. Conciliant lines of evidence indicate their deployment against invasive entities, like viruses, to limit their spread in multicellular/social contexts via physical containment, dominant-negative interactions or apoptosis. Base on these findings we argue for both a similar operational 'grammar' and shared protein domains in the sensing and limiting of infections during the multiple emergences of multicellularity.
Terms: <2019 novel coronavirus><2019-nCoV><Active Sites><Animals><Antimorphic mutation><Apoptosis><Apoptosis Pathway><Architecture><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bacteria><Binding><Biochemistry><Biological><Biological Chemistry><Biological Function><Biological Process><Biology><COVID-19><COVID19><Calcineurin><Calcium><Cell Body><Cell Communication and Signaling><Cell Function><Cell Locomotion><Cell Migration><Cell Movement><Cell Process><Cell Signaling><Cell physiology><Cells><Cellular Function><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Chaperone><Class Switching><Class Switchings><CoV emergence><Collaborations><Complex><Conflict><Conflict (Psychology)><Cysteine><DIDMOAD><DNA><DNA Binding><DNA Binding Interaction><DNA Damage Repair><DNA Double Strand Break><DNA Repair><DNA bound><Defect><Deoxyribonucleic Acid><Dominant Negative><Dominant-Negative Mutant><Dominant-Negative Mutation><Double Strand Break Repair><EC 2.7.7.49><EF Hand Motifs><EF Hands><ES cell><Endoplasmic Reticulum><Engineering / Architecture><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Ergastoplasm><Esteroproteases><Eukaryota><Eukaryote><Evolution><Family><GTP Phosphohydrolases><GTPases><Gene Family><Genes><Genome><Genomics><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><Half-Cystine><Hematopoiesis><Hematopoietic Cellular Control Mechanisms><Hereditary><Human><Immune Globulins><Immune response><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin Domain><Immunoglobulin Isotype-Switch Recombination><Immunoglobulin Switch Recombination><Immunoglobulin-Like Domain><Immunoglobulins><Immunological response><Infection><Inherited><Intracellular Communication and Signaling><Isotype Switching><Isotype Switchings><L-Cysteine><Ligand Binding><Lung diseases><Measures><Mediating><Mice><Mice Mammals><Microscopic><Mitochondria><Modern Man><Modification><Molecular Chaperones><Molecular Interaction><Motility><Murine><Mus><NTPase><Nucleic Acids><Nucleoside Triphosphate Phosphohydrolase><Nucleosidetriphosphatase><PP2B><Pathogenesis><Pathogenicity Factors><Pathway interactions><Peptidases><Peptide Domain><Peptide Hydrolases><Phosphoprotein Phosphatase><Phosphoprotein Phosphatase-2C><Phosphoprotein Phosphohydrolase><Physical Containment><Position><Positioning Attribute><Process><Programmed Cell Death><Prokaryotae><Prokaryotic Cells><Protease Gene><Proteases><Protein Domains><Protein Phosphatase C><Protein Phosphatase Gene><Protein Phosphatase-1><Protein Phosphatase-2A><Protein Phosphatase-2B><Protein phosphatase><Proteinases><Proteins><Proteolytic Enzymes><Pulmonary Diseases><Pulmonary Disorder><RNA Transcriptase><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><Reporting><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Reverse Transcriptase><Revertase><Risk><Role><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><SOS Function><SOS Induction><SOS Repair><SOS Response><SOS System><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe acute respiratory syndrome coronavirus 2><Signal Transduction><Signal Transduction Systems><Signaling><Site><Social Environment><Structure><Subcellular Process><Switch Recombination><System><Tertiary Protein Structure><Time><Transmission><Triad><Triad Acrylic Resin><Triad resin><Unscheduled DNA Synthesis><Virulence Factors><Virus><WFS1><WFS1 gene><Wolfram Syndrome><Wolframin><Work><Wuhan coronavirus><base><biological signal transduction><biomineralization><blood cell formation><cell motility><comparative genomics><corona virus disease 2019><coronavirus disease 2019><coronavirus emergence><cross-link><crosslink><diabetes insipidus and mellitus with optic atrophy and deafness><diabetes insipidus-diabetes mellitus-optic atrophy syndrome><disease of the lung><disorder of the lung><embryonic stem cell><emergent CoV><emergent coronavirus><emerging CoV><emerging coronavirus><entire genome><full genome><global health><guanosinetriphosphatase><host response><immunoresponse><innovate><innovation><innovative><lung disorder><mitochondrial><nCoV><new CoV><new coronavirus><novel><novel CoV><novel coronavirus><nucleoside triphosphatase><pathway><progenitor><prokaryote><recruit><response><severe acute respiratory syndrome-CoV><social><social climate><social context><social role><socioenvironment><socioenvironmental><stem><stem cell of embryonic origin><symbiont><transmission process><whole genome>